ChemPath: Brief Lipid Update

Question 1

What is the optimal medical therapy for people with coronary heart disease?

Answer 1

• Intensive lifestyle modification
• Aspirin
• High-dose statin (atorvastatin 40-80mg OD)
• Optimal blood glucose control
• Thiazides (reduce fluid overload/afterload, bp control)
• Assessment for probable T2DM

Question 2

What is the statistical mortality benefit of adding a thiazide diuretic to outstanding BP medications, following an MI?

Answer 2

Worth it, as 2 in 100 will be prevented from a further MI in the next 5 years

Shown by the SPRINT Study

Question 3

List some options for people with statin intolerance.

Answer 3

• Ezetemibe (inhibit NPC1L1r, hence si uptake of cholesterol)
• PCSK9 inhibitors
• Plasma exchange

NOTE: niacin/nicotinic acid is no longer available

Question 4

Describe the function of PCSK9

Answer 4

• PCSK9 binds the LDL receptor leading to endocytosis and their degradation
• This reduces the ability of the liver to take up cholesterol from the blood
  ** Hence gain of function mutation of PCSK9: increase rate of degradation of LDL receptor -> therefore LDL cannot bind to liver -> increased LDL
  ** Loss of function mutation: slower rate of degradation of LDL receptor -> increased binding of LDL to liver -> decreased LDL

Question 5

Name a PCSK9 inhibitor.

Answer 5

Evolocumab

Question 6

Which patient group may benefit from PCSK9 inhibitors?

Answer 6

Patients who are at very high risk (e.g. familial hypercholesterolaemia)

Statin-intolerant patients

NOTE: PCSK9 inhibitors reduce the incidence of cardiovascular events but has no effect on mortality, and has a high NNT (Fourier study)

Question 7

How long does it take to see benefit from good glucose control?

Answer 7

15 years to see a reduction in complications

Shown by the UKPDS (UK Prospective Diabetes Study) study 1998

Question 8

What is the legacy effect?

Answer 8

A period of good glycaemic control will have a beneficial effect on mortality for up to 10 years even if the patient reverts to poor glycaemic control after a certain period of time.

Shown by the UKPDS study

Question 9

What did the DCCT trial show?

Answer 9

Good control in type 1 diabetes improves outcomes

*Legacy effect was shown here too*

Question 10

What did the Advance study show?

Answer 10

Targeting HbA1c of less than 6.5% (47.5 mmol/mol) reduces microvascular, macrovascular events & death

Intensive glucose control was associated with an increased risk of severe hypoglycaemia and hospitalisation BUT no increased risk of mortality (unlike Accord study)

Question 11

What are the effects of sudden aggressive blood glucose control in patients with long-standing poor glycemic control and cardiovascular complications?

Answer 11

• Reduced the incidence of complications
• Increased mortality (sudden hypoglycaemia + hypokalaemia from t2dm drugs -> tachycardia, arrhythmias)!!

Really important to consider whether the patient has atheromas to begin with before suddenly tightening glucose control

This was found by the ACCORD trial

Question 12

Describe how SGLT2 inhibitors can reduce blood glucose.

Answer 12

Increases urinary excretion of glucose from PCT, causing a reduction in blood glucose and blood pressure.

NOTE: this can also be used in heart failure because of its diuretic effect

Main side-effects: UTIs due to glycosuria, rarely DKA

Question 13

Name an SGLT2 inhibitor

Answer 13

Empagliflozin

Question 14

What were the key findings of the EMPA-REG study?

Answer 14

Investigating empagliflozin effect on CVD outcomes in pts with T2DM

Significant reduction in mortality after just 4 years

Reduces HbA1c

Lowers hospitalisation due to heart failure (due to diuresis)

Prevents nephropathy as it reduces albuminuria by letting glucose pass into the tubules instead - protects the kidneys
- initial sharp reduction in GFR but then recovers
- slows rate of eGFR decline

*Albumin is poisonous to the kidneys so these SGLT2 inhibitors are renal-protective*

Question 15

What is the physiological role of GLP1?

Answer 15

• Produced by the gut and signals to the pancreas to produce more insulin (incretin effect)
• Also has a direct effect on satiety and gastric emptying

Question 16

What breaks down GLP1?

Answer 16

DPP4

Question 17

Which class of drugs inhibits the breakdown of GLP1?

Answer 17

Gliptins (by inhibiting DPP4 and, thereby, preventing the breakdown of GLP1)

Likely to be phased out as GLP-1 analogues work better

Question 18

List three examples of GLP1 analogues.

Answer 18

• Exanatide (synthetic version of exendin 4)
• Liraglutide (saxenda)
• Semaglutide

All injections at the moment so SGLT2 inhibitors are preferred in combination with metformin

Question 19

Summarise the steps in the pharmacological management of type 2 diabetes mellitus.

Answer 19

1. Metformin
2. if non-insulin monotherapy at maximum tolerated dose does not achieve or maintain the HbA1c target after 3 months add either:
   
   • Second oral agent OR
   • GLP1 agonist OR
   • Basal insulin

In patients with long-standing suboptimally controlled T2DM and established cardiovascular disease, empagliflozin (SGLT2 inhibitor) or liraglutide (GLP1 analogue) should be considered.

Question 20

Key findings from UKPDS study

Answer 20

Need 15 years of good gluc control to see reduction in complications

Legacy effect

Question 21

Key finding from ACCORD study

Answer 21

Sudden tight glucose control in pts with long standing hyperglycemia results in increased mortality

(sudden hypoglycaemia + hypokalaemia from t2dm drugs -> tachycardia, arrhythmias)!!

Hence Really important to consider whether the patient has atheromas to begin with before suddenly tightening glucose control*